WO2017071576A1 - 稠和杂环类化合物衍生物及其应用 - Google Patents

稠和杂环类化合物衍生物及其应用 Download PDF

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Publication number
WO2017071576A1
WO2017071576A1 PCT/CN2016/103329 CN2016103329W WO2017071576A1 WO 2017071576 A1 WO2017071576 A1 WO 2017071576A1 CN 2016103329 W CN2016103329 W CN 2016103329W WO 2017071576 A1 WO2017071576 A1 WO 2017071576A1
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WIPO (PCT)
Prior art keywords
quinoline
fluorobenzoisoxazole
piperazin
dihydro
group
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PCT/CN2016/103329
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English (en)
French (fr)
Chinese (zh)
Inventor
张桂森
曹旭东
陈寅
张译芳
于民权
邱印利
徐祥清
张探
刘笔锋
刘欣
Original Assignee
江苏恩华药业股份有限公司
武汉珈瑜科技有限公司
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Application filed by 江苏恩华药业股份有限公司, 武汉珈瑜科技有限公司 filed Critical 江苏恩华药业股份有限公司
Priority to US15/771,225 priority Critical patent/US10517862B2/en
Priority to CN201680062480.1A priority patent/CN108368106B/zh
Priority to JP2018522505A priority patent/JP6786599B2/ja
Priority to EP16859011.5A priority patent/EP3372600B1/en
Publication of WO2017071576A1 publication Critical patent/WO2017071576A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and in particular relates to the synthesis and application of a fused heterocyclic compound derivative. More particularly, the present invention relates to a fused heterocyclic compound derivative, a pharmaceutical composition comprising the fused heterocyclic compound derivative, and a pharmaceutical composition and the fused heterocyclic compound derivative in the preparation of prevention Or use in medicines for the treatment of neuropsychiatric disorders.
  • Schizophrenia is a disease characterized by deep division of cognition and emotion, manifested by the most basic human behaviors such as language, thought, perception, and self-perception. Symptoms of the disease include a wide range of symptoms, the most common being mental disorders such as hallucinations, delusions and illusions. Schizophrenia is the most serious mental illness. About 1% of people worldwide suffer from schizophrenia, and only 5% of all treated patients eventually recover completely. In addition, schizophrenia usually causes comorbidities such as anxiety disorders, depression or psychotropic substance abuse. According to a survey conducted by Datamonitor, more than one-third of people with schizophrenia suffer from at least one or more concurrent diseases such as mental illness or cognitive impairment.
  • antipsychotic drugs that exert pharmacological effects by blocking dopamine D 2 receptors are called first-generation antipsychotics, ie, "typical” antipsychotics (such as haloperidol), which treat positive symptoms of schizophrenia. Breakthrough, but failed to treat negative symptoms and cognitive impairment.
  • Typical antipsychotic drugs generally have severe EPS (pyramidal) side effects and are ineffective for one-third of patients with schizophrenia.
  • Aripiprazole is a phenbutyrazine compound that was approved by the FDA in November 2002.
  • the drug has a unique mechanism of action and has high affinity with dopamine D 2 , D 3 , 5-HT 1A and 5-HT 2A receptors, with D 4 , 5-HT 2c , 5-HT 7 , ⁇ 1 ,
  • the H 1 receptor and 5-HT reabsorption sites have moderate affinity.
  • Aripiprazole produces anti-schizophrenia effects by partial agonism of D 2 and 5-HT 1A receptors and antagonism of 5-HT 2A receptors, and has an effect of stabilizing dopamine system activity.
  • the serotonin system plays an important role in the regulation of the function of the prefrontal cortex (PFC), including mood control, cognitive behavior, and working memory.
  • PFC pyramidal neurons and GABA interneurons contain several 5-HT 1A and 5-HT 2A with particularly high-density serotonin receptor subtypes.
  • the PFC and NMDA receptor channels have recently been shown to be targets of 5-HT1AR, which regulate cerebral cortical excitatory neurons and thereby affect cognitive function.
  • 5-HT1AR may be a new target for the development of antipsychotic drugs.
  • atypical antipsychotic drugs such as olanzapine, aripiprazole, etc.
  • 5-HT1AR prefrontal cortex
  • PFC pyramidal neurons and GABA interneurons contain several 5-HT 1A and 5-HT 2A with particularly high density serotonin receptor subtypes.
  • 5-HT1A agonists are associated with atypical antipsychotic treatments that improve negative symptoms and cognitive impairment.
  • 5-HT 2A has been found to play an important role in all aspects of perception, mood regulation and motor control. Blocking the 5-HT 2A receptor normalizes the release of dopamine and acts as an antipsychotic.
  • the 5-HT 2C receptor is closely related to weight gain.
  • the distribution of D 3 receptor in the brain is mainly selectively distributed in the limbic system.
  • the prefrontal cortex DA pathway in the nucleus accumbens is closely related to learning cognitive and emotional activities. Its dysfunction will lead to schizophrenia.
  • the DA pathway is also the main pathway for reward effect in the brain.
  • D3R is in the two DA neural pathways.
  • the selective D3 receptor antagonism can reduce the negative and cognitive symptoms of schizophrenia. In addition, it can prevent extrapyramidal side effects, including tardive dyskinesia, Parkinson's disease.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt or prodrug thereof,
  • Z is an unsubstituted or -(CH 2 ) m -, m substituted by one or more substituents selected from the group consisting of a hydroxyl group, a carbonyl group and a C 1-5 alkyl group (such as a methyl group), m is an integer of from 2 to 5;
  • Y is O or S
  • Q is N or CH
  • n 1, 2 or 3;
  • R 1 , R 2 , R 3 or R 4 are each independently hydrogen, halogen, unsubstituted or C 1-5 alkyl substituted by one or more substituents selected from the group consisting of halogen, amino and hydroxy;
  • R is a group of a phenyl group, a formula (II), a formula (III) or a formula (IV), and the above group may be unsubstituted or one or more selected from the group consisting of halogen, cyano and C 1-5 alkyl a C 1-5 alkoxy group (such as a methoxy group) and a substituent in the hydroxy group;
  • X is O or S; and R 5 is H or halogen.
  • Z is a substituted group unsubstituted or substituted with one or more substituents selected from hydroxyl, a carbonyl group and a methyl group - (CH 2) m -, m is 2 to An integer of 5.
  • the halogen is fluorine, chlorine, bromine or iodine.
  • R in formula (I) is a group of formula (II), wherein when X is O, R 5 is selected from the group consisting of fluorine, chlorine, bromine and iodine; when X is S, R 5 is hydrogen.
  • R in formula (I) is substituted by one or more selected from the group consisting of methoxy, methyl, ethyl, ethyl fluoride, fluorine, chlorine, bromine, iodine and cyano.
  • a substituted phenyl group is substituted by one or more selected from the group consisting of methoxy, methyl, ethyl, ethyl fluoride, fluorine, chlorine, bromine, iodine and cyano.
  • R 1 , R 2 , R 3 or R 4 in formula (I) are each independently hydrogen, phenyl, halophenyl, C 1-5 alkyl, halo C 1-5 alkyl or C 1-5 hydroxyalkyl; preferably, R 1 , R 2 , R 3 or R 4 are each independently hydrogen, fluoro, phenyl, methyl, ethyl, propyl, trifluoro Methyl or hydroxymethyl.
  • Z of the formula (I) is -(CH 2 ) m - which is unsubstituted or substituted by one or more substituents selected from the group consisting of a hydroxyl group and a carbonyl group, and m is an integer of from 2 to 5. .
  • Y is O or S
  • Q is N or CH
  • n 1, 2 or 3;
  • R 1 , R 2 , R 3 or R 4 are each independently hydrogen, fluoro, phenyl, methyl, ethyl or propyl;
  • R is a phenyl group, a group of formula (III) or a group of formula (IV);
  • R is a group of the formula (II), wherein when X is O, R 5 is selected from fluorine and chlorine, or when X is S, R 5 is hydrogen;
  • R is a phenyl group substituted by one or more substituents selected from the group consisting of methoxy, methyl, ethyl, ethyl fluoride, fluorine, chlorine, bromine and cyano.
  • the invention relates to at least one of the following compounds or a stereoisomer, tautomer, oxynitride, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof:
  • the present invention is also a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof, optionally further comprising a pharmaceutically acceptable excipient, carrier, Agent, vehicle or a combination thereof.
  • the compound of the present invention or a pharmaceutically acceptable salt or prodrug thereof or the pharmaceutical composition of the present invention can be used for the prevention or treatment of a psychiatric disorder.
  • the invention also relates to a method of preventing or treating a psychiatric disorder, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof or a medicament of the invention combination.
  • the invention further relates to the use of a compound of the invention, or a pharmaceutically acceptable salt or prodrug thereof, or a pharmaceutical composition of the invention, for the manufacture of a medicament for the prevention or treatment of a psychiatric disorder.
  • the psychotic disorder is schizophrenia.
  • patient or “individual” as used herein refers to a human (including adults and children) or other animals (including mammals). According to some embodiments of the invention, “patient” or “individual” refers to a person.
  • the compounds of the invention may be optionally substituted with one or more substituents, such as the compounds of the above formula or specific examples, subclasses as in the examples.
  • substituents such as the compounds of the above formula or specific examples, subclasses as in the examples.
  • substituents such as the compounds of the above formula or specific examples, subclasses as in the examples.
  • substituents such as the compounds of the above formula or specific examples, subclasses as in the examples.
  • substituents such as the compounds of the above formula or specific examples, subclasses as in the examples.
  • C 1-5 alkyl refers specifically to the independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, and C 5 alkyl groups.
  • alkyl groups include, but are not limited to, methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), n-propyl (n-Pr, -CH 2 CH 2 CH 3 ), Propyl (i-Pr, -CH(CH 3 ) 2 ), n-butyl (n-Bu, -CH 2 CH 2 CH 2 CH 3 ), isobutyl (i-Bu, -CH 2 CH (CH 3 ) 2 ), sec-butyl (s-Bu, -CH(CH 3 )CH 2 CH 3 ), tert-butyl (t-Bu, -C(CH 3 ) 3 ), n-pentyl (-CH 2 CH 2 ) CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3 )CH 2 CH 2 CH 3 ), 3-pentyl (-CH(CH 2 CH 3 ) 2 ), 2-methyl-2- Butyl (-C(CH 3 ) 2
  • Ranges (such as ranges of values) recited herein can encompass each of the ranges and the various sub-ranges formed by the various values. Therefore, the expression “m is an integer of 2 to 5” includes, for example, an integer of 2 to 4, an integer of 3 to 5, and the like, for example, 2, 3, 4, and 5.
  • one or more may mean 1, 2, 3, 4, 5, 6 or more.
  • hydrox (H) means a single hydrogen atom. Such radicals may be attached to other groups, such as to an oxygen atom, to form a hydroxyl group.
  • halogen means fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
  • alkoxy denotes an alkyl group attached to the remainder of the molecule through an oxygen atom, wherein the alkyl group has the meaning as described herein. Unless otherwise specified, the alkoxy group may contain from 1 to 12 carbon atoms. According to one embodiment of the invention, the alkoxy group may contain from 1 to 6 carbon atoms. According to another embodiment of the invention, the alkoxy group may contain from 1 to 5 or from 1 to 4 carbon atoms. According to still another embodiment of the present invention, the alkoxy group may have 1 to 3 carbon atoms. The alkoxy group is optionally substituted with one or more substituents described herein.
  • alkoxy groups include, but are not limited to, methoxy (MeO, -OCH 3 ), ethoxy (EtO, -OCH 2 CH 3 ), 1-propoxy (n-PrO, n- Propyloxy, -OCH 2 CH 2 CH 3 ), 2-propoxy (i-PrO, i-propoxy, -OCH(CH 3 ) 2 ), 1-butoxy (n-BuO, n- Butoxy, -OCH 2 CH 2 CH 2 CH 3 ), 2-methyl-l-propoxy (i-BuO, i-butoxy, -OCH 2 CH(CH 3 ) 2 ), 2-butyl Oxygen (s-BuO, s-butoxy, -OCH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC(CH) 3 ) 3 ), 1-pentyloxy (n-pentyloxy, -OCH 2 CH 2 CH 2 CH 2 CH
  • ring includes carbocyclic, heterocyclic, aromatic, heteroaryl, and the like, wherein the carbocyclic, heterocyclic, aromatic, heteroaryl ring group has the meaning as described herein.
  • cycloalkyl denotes a monovalent or polyvalent saturated monocyclic, bicyclic or tricyclic ring system containing from 3 to 12 carbon atoms. Bicyclic or tricyclic systems can include fused rings, bridged rings, and spiro rings. According to one embodiment of the invention, the cycloalkyl group may contain from 3 to 10 carbon atoms. According to another embodiment of the invention, the cycloalkyl group may contain from 3 to 8 carbon atoms. According to still another embodiment of the present invention, the cycloalkyl group may contain 3 to 6 carbon atoms.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the cycloalkyl group is optionally substituted with one or more substituents described herein.
  • aryl denotes a monocyclic, bicyclic and tricyclic carbocyclic ring system containing from 6 to 14 ring atoms, or from 6 to 12 ring atoms, or from 6 to 10 ring atoms, wherein at least one ring is aromatic .
  • the aryl group is typically, but not necessarily, attached to the parent molecule through an aromatic ring of the aryl group. Examples of the aryl group may include a phenyl group, a naphthyl group, and an anthracene.
  • the aryl group is optionally substituted with one or more substituents described herein.
  • prodrug denotes a compound which can be converted in vivo to a compound of the formula (I). Such transformation is affected by the hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue.
  • prodrugs can be found in the following literature: Higuchi et al., Pro-drugs as Novel Delivery Systems, Vol.
  • metabolite refers to a product obtained by metabolism of a specific compound or a salt thereof in vivo. Metabolites of the compounds can be identified by techniques well known in the art, the activity of which can be characterized by experimental methods as described herein. Such products can be obtained by subjecting the administered compound to oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage and the like. Accordingly, the invention encompasses metabolites of the compounds of the invention, such as those produced by the compounds of the invention in sufficient contact with a mammal for a period of time.
  • the present invention also encompasses stereoisomers, tautomers, nitrogen oxides, solvates (e.g., hydrates), metabolites, and the like of the compounds of the present invention or salts thereof. These forms are preferably pharmaceutically acceptable.
  • the "pharmaceutically acceptable salt” as used in the present invention means an organic salt and an inorganic salt of the compound of the present invention.
  • Pharmaceutically acceptable salts are well known in the art as described in the literature: SM Berge et al., J. Pharmaceutical Sciences, 66: 1-19, 1977.
  • Salts formed by pharmaceutically acceptable non-toxic acids include, but are not limited to, salts formed by reaction with inorganic acids, such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates; a salt formed by the reaction of an organic acid, such as acetate, oxalate, maleate, tartrate, citrate, succinate, malonate, or other methods such as ion exchange as described in the literature.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, besylate, benzoate, disulfate, borate, butyrate , camphorate, camphor sulfonate, cyclopentyl propionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate , glycerol phosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl Sulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, pers
  • Salts obtained by appropriate bases include, but are not limited to, alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • the invention also encompasses quaternary ammonium salts formed from compounds of any of the groups comprising N. Water soluble or oil soluble or dispersed products can be obtained by quaternization.
  • the alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium salts, and the like.
  • Pharmaceutically acceptable salts further comprise suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion, such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • suitable amine cation nontoxic ammonium, quaternary ammonium, and the counterion such as halide, hydroxide, carboxylate, sulfated, phosphorylated compounds, nitrate compounds, C 1 -8 sulfonate and aromatic sulfonate.
  • the compounds provided by the invention have strong affinity for D 2 , D 3 , 5HT 1A and/or 5HT 2A , have the potential to improve the positive symptoms of schizophrenia, and have potential improvement effects on negative symptoms and cognitive disorders. .
  • the compounds provided by the present invention have low affinity for 5HT 2C , H 1 and/or ⁇ 1 and thus have the advantage of a reduced weight gain effect. Animal experiments have shown that the compounds of the invention have less extrapyramidal side effects.
  • a general synthetic method for the compounds of the present invention can include first synthesizing a tricyclic fused precursor, then reacting it with a linear chloroformyl chloride and then reacting with the nitrogen terminus.
  • the title compound was prepared in the same manner as in Example 1, except that 3-chloropropanoyl chloride was used instead of 2-chloroacetyl chloride.
  • Example 2 The title compound (0.5 g) of Example 2 was obtained, and the mixture was dissolved in trifluoroacetic acid (20 mL), and triethylsilane (0.10 g) was slowly added to the mixture and stirred at room temperature overnight. The solvent was evaporated to dryness, adding an appropriate amount of dichloromethane, washed with saturated NaHCO 3 solution, layer of water. The organic layer was dried over anhydrous magnesium sulfate was added, solvent was evaporated to give a pale yellow oil. Column chromatography gave a colorless transparent oil (0.35 g).
  • the title compound was prepared in the same manner as in Example 1, except that 4-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 3 except that the target compound of Example 5 was used instead of the target compound of Example 2.
  • the title compound was prepared in the same manner as in Example 4 except that the target compound of Example 5 was used instead of the target compound of Example 2.
  • the title compound was prepared in the same manner as in Example 1 except that 5-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 4 except that the target compound of Example 9 was used instead.
  • the title compound was prepared in the same manner as in Example 1, except that porphyrin was used in place of 1,2,3,4-tetrahydroquinoline.
  • the title compound was prepared in the same manner as in Example 1, except that porphyrin was used in place of 1,2,3,4-tetrahydroquinoline, and 2-chloropropanoyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 3 except that the target compound of Example 12 was used instead.
  • the target compound was prepared in the same manner as in Example 4 except that the target compound of Example 12 was used instead of Example 2. Target compound.
  • the title compound was prepared in the same manner as in Example 1, except that porphyrin was used in place of 1,2,3,4-tetrahydroquinoline, and 4-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 3 except that the target compound of Example 15 was used instead.
  • the title compound was prepared in the same manner as in Example 4 except that the target compound of Example 15 was used instead.
  • the title compound was prepared in the same manner as in Example 1, except that porphyrin was used in place of 1,2,3,4-tetrahydroquinoline, and 5-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared according to the method of Example 3, and the target compound of Example 2 was replaced with the target compound of Example 17.
  • Example 20 8-(5-(4-(3-(6-fluorobenzoisoxazole)-1-piperidyl)pentyl)-5,6-dihydro-1H-pyrrole [3,2 , 1-ij]-quinoline-4(2H)-one.
  • the title compound was prepared in the same manner as in Example 4 except that the target compound of Example 17 was used instead.
  • the title compound was prepared in the same manner as in Example 1 except that 4-fluoroporphyrin was used in place of 1,2,3,4-tetrahydroquinoline, and 2-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 1 except that 6-fluoroporphyrin was used in place of 1,2,3,4-tetrahydroquinoline, and 4-chloroacetyl chloride was used instead of 2-chloroacetyl chloride.
  • the title compound was prepared in the same manner as in Example 23 except that 1-(2-methoxyphenyl)piperazine was used instead of 1-phenylpiperazine.
  • the title compound was prepared in the same manner as in Example 23 except that 1-(2,3-dimethylphenyl)piperazine hydrochloride was used instead of 1-phenylpiperazine.
  • the title compound was prepared in the same manner as in Example 23 except that 1-(2,3-dichlorophenyl)piperazine hydrochloride was used instead of 1-phenylpiperazine.
  • the title compound (0.5 g) from m.
  • the solvent was evaporated to dryness, adding an appropriate amount of dichloromethane, washed with saturated NaHCO 3 solution, to the water layer.
  • the organic layer was dried over anhydrous magnesium sulfate and evaporated.
  • the title compound was prepared in the same manner as in Example 23 except that 1-(4-(benzo[d]isothiazol-3-yl)piperazine was used instead of 1-phenylpiperazine.
  • the title compound was prepared according to the procedure of Example 23 except that 4-chloropropanoyl chloride was used instead of 3-chloropropanoyl chloride, and 1-(2,3-dimethylphenyl)piperazine hydrochloride was used instead of 1-phenylpiperazine. .
  • the title compound was prepared according to the method of Example 30, except that the target compound of Example 29 was used instead.
  • the title compound was prepared according to the method of Example 30, except that the target compound of Example 29 was used instead of the target compound of Example 29.
  • the target compound was prepared as in Example 23 except that porphyrin was used instead of 1,2,3,4-tetrahydroquinoline.
  • 1-(2,3-Dimethylphenyl)piperazine was substituted for 1-phenylpiperazine.
  • the title compound was prepared in the same manner as in Example 38 except that 1-(2,3-chlorophenyl)piperazine was used instead of 1-(2,3-dimethylphenyl)piperazine.
  • the title compound was prepared according to the method of Example 31 except that the target compound of Example 40 was used instead of the target compound of Example 8.
  • the title compound was prepared according to the procedure of Example 23 except that 4-chloropropanoyl chloride was used instead of 3-chloropropanoyl chloride, and 1-(2,3-dichlorophenyl)piperazine was used instead of 1-phenylpiperazine.
  • the title compound was prepared according to the method of Example 30, except that the target compound of Example 29 was used instead of the target compound of Example 29.
  • the title compound was prepared according to the method of Example 30, except that the target compound of Example 29 was used instead of the target compound of Example.
  • the homogenate used includes A homogenate, B homogenate, C homogenate, E homogenate and F homogenate, and the configuration methods are as follows:
  • the A homogenate contained a final concentration of 0.01 M Tris-HCl buffer and a final concentration of 0.32 M sucrose solution at a pH of 7.4.
  • the B homogenate was a 0.01 M Tris-HCl buffer with a pH of 7.4.
  • the C homogenate was 50 mM Tris buffer and had a pH of 7.4.
  • Rats were decapitated, operated on ice, and the striatum was quickly taken. Two striatum were combined into a centrifuge tube, and 3 ml of buffer (0.05 M Tris-HCl buffer containing 0.1% ascorbic acid, 10um excellent descending Ning and 4mM CaCl 2 ), homogenized in 4th gear for 3-4s, homogenized 4 times. Then, 5 ml of buffer (0.05 M Tris-HCl buffer containing 0.1% ascorbic acid, 10 um eugenin and 4 mM CaCl 2 ) was added, and the mixture was incubated at 37 ° C for 10 min. After the incubation, the test tube was adjusted in weight with a balance.
  • buffer 0.05 M Tris-HCl buffer containing 0.1% ascorbic acid, 10um excellent descending Ning and 4mM CaCl 2
  • Isotope ligand 3 H-8-OH-DPAT (67.0 Ci/mmol) was purchased from PerkinElmer; 5-HT was purchased from RBI; GF/C glass fiber filter paper was purchased from Whatman; Tris imported package; PPO, POPOP purchased Since Shanghai Reagent No. 1; fat-soluble scintillation fluid was purchased from Shanghai Reagent Factory. Beckman LS-6500 multi-function liquid scintillation counter.
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • Rats were decapitated, operated on ice, and the striatum was quickly taken. Two striatum were combined into a centrifuge tube, and 3 ml of buffer (0.05 M Tris-HCl buffer: 6.05 g of Tris dissolved in 1000 ml) was added. In double distilled water, adjust the pH to 7.5 with concentrated HCl) and homogenize for 3-4 s in 4 steps, and homogenize 4 times. Then 5 ml of buffer was added and incubated at 37 ° C for 10 min. After the incubation, the test tube was adjusted to a weight with a balance, centrifuged, and the supernatant was discarded. 3 ml of the A homogenate was added, mixed with a vortex mixer, and 5 ml of a buffer was added. After centrifugation, the supernatant was discarded and the pellet was stored at -80 ° C until use.
  • buffer 0.05 M Tris-HCl buffer: 6.05 g of Tris dissolved in
  • the isotope ligand [ 3 H]-Ketanserin (67.0 Ci/mmol) was purchased from PerkinElmer; Methysergide was purchased from RBI; GF/C glass fiber filter was purchased from Whatman; Tris was dispensed; PPO and POPOP were purchased from Shanghai Reagent Factory; fat-soluble scintillation fluid purchased from Shanghai Reagent Factory; Beckman LS-6500 multi-function liquid scintillation counter.
  • the prepared membrane was uniformly dispersed by a homogenizer through a homogenizer, and 15 tubes were mixed into a 100 ml container, and an appropriate amount of A homogenate was added to obtain a suspension of 50 ml of the membrane, which was used.
  • reaction tube was separately added with 100 ⁇ L of the membrane preparation and 100 ⁇ L of the buffer.
  • Total binding tube (TB) was added to 100 ⁇ L homogenate, non-specific binding tube (NB) was added to Methysergide 100 ⁇ L (final concentration 10 -5 M), and each test compound specific binding tube (SB) was added with 100 ⁇ L of test compound (final Concentration 10 -5 M);
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • Rats were decapitated, operated on ice, and the striatum was quickly taken. Two striatum were combined into a centrifuge tube, and 3 ml of buffer (0.05 M Tris-HCl buffer containing NaCl 120 mM, KCl 5 mM) was added. , MgCl 2 1 mM, CaCl 2 1 mM), homogenate in 4 steps for 3-4 s, homogenate 4 times, then add 5 ml of buffer.
  • buffer 0.05 M Tris-HCl buffer containing NaCl 120 mM, KCl 5 mM
  • the isotopic ligand 3 H-Spiperone (67.0 Ci/mmol) was purchased from PerkinElmer; Butaclamol was purchased from RBI; GF/C glass fiber filter paper was purchased from Whatman; Tris was imported; PPO and POPOP were purchased from Shanghai Reagent 1; The fat-soluble scintillation fluid was purchased from Shanghai Reagent Factory; Beckman LS-6500 multi-function liquid scintillation counter.
  • the prepared membrane was uniformly dispersed by a homogenizer through a homogenizer, and 15 tubes were mixed into a 100 ml container, and an appropriate amount of B homogenate was added to obtain a suspension of 50 ml of the membrane, which was used.
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • the receptor protein was expressed on the membrane after 48-72 hours.
  • the cells were centrifuged at 1000 rpm for 5 min, and the supernatant was discarded.
  • the cells were harvested and stored in a refrigerator at -20 °C. Resuspend with Tris-Cl (pH 7.4) during the experiment.
  • D 3 receptor isotope [ 3 H]-Spiperone was purchased from Amersham; (+) Butaclamol was purchased from RBI; GF/C glass fiber filter was purchased from Whatman; fat soluble scintillation was purchased from Shanghai Reagent; Beckman LS -6500 multi-function liquid scintillation counter; Tris is packaged by Jitai Technology Co., Ltd.
  • Receptor competition binding assay 20 ⁇ l of each test compound and radioactive ligand and 160 ⁇ l of receptor protein were added to the reaction tube, so that the final concentration of the test compound and the positive drug was 10 ⁇ mol/L. After incubation for 50 min in a 30 ° C water bath, the reaction was immediately stopped by moving to an ice bath. On a Millipore cell sample collector, rapidly filtered through GF/C glass fiber filter paper, and eluted 3 times with 3 ml of eluent (50 mM Tris-HCl, pH 7.4), dried in a microwave oven for 4-5 min, and the filter paper was transferred.
  • eluent 50 mM Tris-HCl, pH 7.4
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • Rats were decapitated, operated on ice, and the striatum was quickly taken. Two striatum were combined into a centrifuge tube, and 3 ml of buffer (0.05 M Tris-HCl buffer: 6.05 g of Tris dissolved in 1000 ml) was added. In double distilled water, adjust the pH to 7.5 with concentrated HCl. Homogenize in 4 steps for 3-4 s and homogenize 4 times. Then add 5 ml of buffer and incubate at 37 ° C for 10 min.
  • buffer 0.05 M Tris-HCl buffer: 6.05 g of Tris dissolved in 1000 ml
  • the isotope ligand [ 3 H]-mesulergine (67.0 Ci/mmol) was purchased from PerkinElmer; the mianserin was purchased from RBI; the GF/C glass fiber filter was purchased from Whatman; the Tris was dispensed; the PPO and POPOP were purchased from Shanghai Reagent Factory; fat-soluble scintillation fluid purchased from Shanghai Reagent Factory; Beckman LS-6500 multi-function liquid scintillation counter.
  • the prepared membrane was uniformly dispersed by a homogenizer through a homogenizer, and 15 tubes were mixed into a 100 ml container, and an appropriate amount of A homogenate was added to obtain a suspension of 50 ml of the membrane, which was used.
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • the rats were decapitated and operated on ice.
  • the rat cerebellum was quickly taken, and the homogenate of F was added, mixed with a vortex mixer, centrifuged at 4 ° C, and the supernatant was discarded to take a precipitate.
  • the F homogenate was further added thereto for washing, and the centrifugation was repeated three times. After centrifugation, the supernatant was discarded, and the precipitate was stored at -80 ° C until use.
  • the prepared membrane was uniformly dispersed by a homogenizer with a proper amount of the F homogenate, and 15 tubes were mixed into a 100 ml container, and an appropriate amount of the F homogenate was added to obtain a suspension of 50 ml of the membrane, which was used.
  • Each reaction tube was separately added to 10 L of a radioligand 3 H-pyrilamine (purchased from PerkinElmer Co., Ltd.) (two parallel tubes were provided for each reaction tube, and each tube was placed on ice when the sample was applied).
  • a radioligand 3 H-pyrilamine purchased from PerkinElmer Co., Ltd.
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • the rats were decapitated, operated on ice, and the brain cortex was quickly taken. E homogenate was added, mixed with a vortex mixer, centrifuged at 48000 g and 4 ° C for 15 min, the supernatant was discarded, and the precipitate was taken, and 0.05 M was added thereto.
  • the Tris-HCl buffer pH 7.7 was washed and centrifuged three times. After centrifugation, the supernatant was discarded and the pellet was stored at -80 ° C until use.
  • the prepared membrane was uniformly dispersed by a homogenizer through a homogenizer, and 15 tubes were mixed into a 100 ml container, and an appropriate amount of E homogenate was added to obtain a suspension of 50 ml of the membrane, which was used.
  • Inhibition rate (I%) (total combined tube cpm - compound cpm) / (total combined tube cpm - non-specific binding tube cpm) ⁇ 100%
  • the compound was subjected to two double tubes per experiment and two separate experiments were performed.
  • Example 54 MK-801 induced high activity: anti-schizophrenia activity of compounds in vivo
  • mice Male and female, weighing (20 ⁇ 2) g, were provided by the Nanjing Qinglongshan Animal Breeding Center.
  • Ascorbic acid was purchased from Sinopharm Chemical Reagent Co., Ltd.;
  • MK-801 is produced by Sigma, USA, and is prepared by formulating 0.1% vitamin C into a 1 mg/ml solution;
  • Positive drugs tested haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine;
  • mice with acceptable body weight were randomly divided into blank group, model group, positive control group (risperidone group) and drug group.
  • the blank group and the model group were intragastrically administered with 10% Tween (0.1 ml/10 g), and the positive control group was administered with risperidone (0.1 mg/kg).
  • the drug group was given the corresponding dose of the drug.
  • the blank group was intraperitoneally injected with 0.1% ascorbic acid (0.1 ml/10 g), and the model group, the positive control group (30 min) and the drug group were intraperitoneally injected with MK-801 solution (0.1 mg/kg). Thereafter, spontaneous activity of each group of mice was measured within 90 minutes. The results are shown in Table 3.
  • Positive drugs tested haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone, quetiapine;
  • Apomorphine is supplied by Sigma and dissolved in 0.9% NaCl (containing 0.1% vitamin C) before use.
  • Vitamin C F20061113, purchased from Sinopharm Chemical Reagent Co., Ltd.;
  • Sodium chloride injection H32026305, was purchased from Xuzhou Fifth Pharmaceutical Factory Co., Ltd.
  • Instrument Homemade climbing cage, stopwatch.
  • mice male, weighing 18-22 g, were randomly divided into negative control group, model group, and positive drug groups (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine, fluoride). Piperidinol, clozapine) and combination Each dose group (see the table below for specific doses), 10 in each group.
  • the negative control group and the model group were given the corresponding solvent double distilled water by gavage, and the positive drug group was given the corresponding positive drug by intragastric administration (first adding a small amount of acetic acid and then adding double distilled water), and each dose group of the compound was intragastrically administered with the corresponding dose of the compound.
  • the volume of the gavage was 0.1 ml/10 g.
  • apomorphine (1 mg/kg) was subcutaneously injected in a volume of 0.1 ml/10 g.
  • the rats were placed in a climbing cage for 5 minutes, and the behaviors of 10-11, 20-21, and 30-31 minutes after the injection of apomorphine were observed and scored. Scoring criteria: Four feet scored 0 on the floor; two forefoot scored 1 on the cage; four feet scored 2 on the cage. The results are shown in Table 3.
  • Example 56 a method of catalepsy
  • Test drug haloperidol, clozapine, risperidone, olanzapine, aripiprazole, ziprasidone
  • Self-made grab bar equipment A stainless steel rod with a diameter of 0.3 cm and a height of 5 cm above the table is placed in the mouse box.
  • mice male and female, weighing 20-24 g, were randomly divided into negative control group, model group and positive drug group (risperidone, aripiprazole, ziprasidone, quetiapine, olanzapine). , haloperidol, clozapine) and compound dose groups, 10 per group.
  • the negative control group and the model group were given the corresponding solvent double distilled water by gavage, and the positive drug group was given the corresponding positive drug by intragastric administration (first adding a small amount of acetic acid and then adding double distilled water), and each dose group of the compound was intragastrically administered with the corresponding dose of the compound.
  • the volume of the gavage was 0.1 ml/10 g.
  • Sequential method limit experiment KM mice, male and female, were randomly divided into several groups, each group of 2-5, each group 2000mg/kg group and solvent group, administered by 0.2ml/10g . Animals were observed for death within 3 days. If the animal survives in 3 or more days within three days and there is no obvious abnormality in the state of life, continue to observe until the end of the experiment after 7 days. If the animal dies 3 or more in three days, the LD 50 is determined by the median lethal dose method.
  • Half-lethal dose method pre-test KM mice, male and female, were randomly divided into several groups, 4 in each group, respectively, each group of 1500mg/kg, 1000mg/kg, 500mg/kg group and solvent group, according to 0.2ml/ 10 g was administered by intragastric administration, and the animals were observed for death within 1-3 days.
  • LD 50 of a single administration of the compound of the present invention was greater than 2000 mg/kg, which was comparable to ziprasidone (>2000 mg/kg), much higher than risperidone (82.1 mg/kg) and Ali. Piperazole (93 mg/kg) has less acute toxicity.
  • compositions of the present invention were prepared according to the following formulations, using the compounds prepared in Examples 1-46 as the active ingredients, respectively, in the form of a tablet dosage form:
  • Excipients are passed through a 80 mesh sieve for use, and the prescribed amount of active ingredient, microcrystalline cellulose, lactose, povidone is weighed. K30, added to the high-speed mixing machine, mix well at low speed, add appropriate amount of purified water, stir at low speed, cut granulation at high speed, then dry the wet granules at 60 ° C for 3 h, sift through 24 mesh, and add the prescribed amount of carboxymethyl Sodium starch, silica and magnesium stearate, total mixing, tableting by rotary tableting machine, that is, a pharmaceutical composition of a tablet dosage form.

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WO2004026864A1 (en) * 2002-09-17 2004-04-01 Warner-Lambert Company Llc Heterocyclic substituted piperazines for the treatment of schizophrenia
WO2008015516A1 (en) * 2006-07-28 2008-02-07 Pfizer Products Inc. Fused tricyclic heterocycles for the treatment of schizophrenia

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JPS56164186A (en) 1980-05-21 1981-12-17 Otsuka Pharmaceut Co Ltd Carbostyril derivative
JP2608788B2 (ja) 1988-10-31 1997-05-14 大塚製薬 株式会社 精神分裂病治療剤
US5006528A (en) 1988-10-31 1991-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
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WO2004026864A1 (en) * 2002-09-17 2004-04-01 Warner-Lambert Company Llc Heterocyclic substituted piperazines for the treatment of schizophrenia
WO2008015516A1 (en) * 2006-07-28 2008-02-07 Pfizer Products Inc. Fused tricyclic heterocycles for the treatment of schizophrenia

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